NEI Support for Corneal Transplantation

Corneal transplants are among the most common and successful transplantation procedures in medicine. Each year approximately 33,000 Americans undergo corneal transplants to replace diseased and injured corneas, the normally crystal clear tissue that protects the eye and helps focus light on the retina. Corneal diseases can cause severe vision impairment. They can also be very painful, making them the most frequent eye-related cause of emergency room visits. For these reasons, corneal transplants are critical to restoring vision and alleviating pain. The failure rate for uncomplicated, or low-risk, corneal grafts, is less than 10 percent. However, in a small subset of high risk patients, where the corneal graft bed is inflamed, failure rates are greater than 50 percent. The National Eye Institute (NEI) is working to understand and overcome rejection in corneal transplantation.

Donor tissue is key to the continued availability of this sight-restoring procedure. However, many eye banks refrain from harvesting tissue from donors over age 65 because of uncertainty about the integrity of older corneas. This practice has been called into question due to concern for the available supply of donor tissue. Meeting the tissue demand for transplantation is always challenging but newly instituted U.S. Food and Drug Administration regulations to further safeguard transplant recipients, and the common use of LASIK surgery to correct refractive errors-which renders corneal tissue unusable for transplantation-could significantly limit future tissue supplies.

The NEI supports a range of grants to improve outcomes for corneal transplantation:

Donor Tissue: The recently published Cornea Donor Study (CDS) found that corneal transplants using tissue from older donors have similar rates of survival to those using tissue from younger donors. In this comprehensive study, which followed 1100 patients, the five-year success rate was 86 percent for both transplants performed with younger corneas from donors ages 12 to 65 years and from older donors ages 66 to 75. Based on these findings, the study authors recommend that the age limit for donor tissue should be expanded to age 75. The CDS study gives eye banks, transplant surgeons and patients confidence in the use of older donor tissue.

Tissue Engineering: Given the concerns for the supply of donor corneal tissue, there has been considerable work to develop a bioengineered cornea. Such a fabricated tissue would alleviate the need for donor tissue. In recent years, laudable attempts have been made to produce corneal equivalents by tissue engineering. These constructs have proven the concept that three layers of cells, resembling the epithelium, keratocytes and endothelium may be cultured into a collagen matrix. However, such constructs have only met with limited success because the stromal matrix, which provides the cornea with its unique (and critically important) mechanical and optical properties, has not been reproduced. Randomly oriented collagen gels, which represent the typical starting point for tissue engineered corneas, are not likely to be strong enough or clear enough for clinical use. For these reasons, NEI-supported investigators are working on a stromal-centric approach for the development of an artificial cornea. Specifically, they are investigating precisely how fibroblastic cells produce organized tissue by tracking human fibroblasts live as they produce a matrix on a long-term live imaging culture system. The next steps in this work are to produce a bioengineered stromal membrane that uses the intelligence already “encoded” into collagen to produce the clear corneal structure. It is hoped these efforts will lead to a clinically useful artificial cornea.

Developing Corneal Endothelial Cells: Bioengineered corneal endothelium is being explored as a practical alternative to corneal transplantation to treat vision loss due to endothelial injury or disease. Currently, donor human corneal endothelial cells (HCEC) are being used to develop bioengineered constructs; however, HCEC have a finite ability to divide, thus limiting the number of healthy cells for use in these constructs. NEI investigators are developing novel approaches to ensure an available supply of healthy HCEC for bioengineered corneal constructs and tissue repair. One approach uses stem cells as they have the potential to differentiate into several cell types. Another approach involves exploiting HCECs through use of various agents known to promote cell proliferation. It is hoped this work will create a reliable source of donor tissue for corneal transplantation.

Immune Mechanisms in High Risk Corneal Transplants: The survival rate of corneal allografts in “high risk” vascularized corneal bed recipients is poor due to immune rejection. It is thought that these grafts are similar to the fate of other solid organ vascularized tissue grafts that require aggressive systemic immune-suppression to improve survival. The rejection of allografts is mediated through the coordinated recruitment and infiltration of allo-specific T cells. Most recently, studies investigating the immunological rejection of solid vascularized organ allotransplants have shown that the early induction of pro-inflammatory chemokines at the site of transplantation is required for the recruitment of immune T cells into rejecting allografts. The recruitment of T cells into the graft is also critical in rejection of high risk vascularized corneal allografts. Rejection correlates to the early production of the chemokine CXCL1/KC and the later up-regulation of T cell chemokines (CXCL9/Mig and CXCL10/IP10). NEI-investigators are evaluating whether inhibition of these chemokines can promote graft survival. The results from this work will identify targets for the development of novel therapeutic reagents and strategies to inhibit T cell infiltration into high risk allografts, and ultimately improve graft survival while decreasing the dependence on debilitating immunosuppressive regimens.

Characterizing Corneal Neovascularization (CN): CN is an established risk factor for corneal allograft rejection and failure. CN compromises the immune privileged status of the cornea and increases the risk of rejection and failure by introducing host immune cells and inflammatory mediators to the allograft. Clinical experience has shown that many patients with corneal transplants have some degree of CN within the host bed yet most allografts survive without incident for many years. Thus, the precise patterns of CN that predict graft morbidity are unknown. Studies of CN have been hampered by the limitations of conventional imaging technologies that do not permit comprehensive quantitation of CN features that predict which patients are at high risk for rejection and failure. The advent of a new imaging technology, confocal biomicroscopy (CBM), provides a new clinical examination method that has the ability to resolve previously undetectable CN and to assess the extent and nature of these lesions. The NEI is supporting clinical research to study CN patterns in human corneal allograft recipients using CBM to determine the characteristics that worsen the prognosis for graft survival. In other work, investigators are evaluating anti-neovascular therapies in the cornea to improve transplant outcomes. This study will provide the basis for identifying those patients for whom such therapy would be warranted.

Preventing Neovascularization and Lymphangiogenesis in the Cornea: The absence of blood and lymphatic vessels in the normal cornea is essential for optical clarity and optimal vision. Numerous eye disorders result in corneal neovascularization that is responsible for blindness in hundreds of millions of individuals worldwide. The vascular endothelial growth factor (VEGF) family and their receptors (VEGFR) are critical elements of the tightly regulated balance of endogenous angiogenesis stimulators and inhibitors, which when disrupted results in neovascularization. The principal positive regulators of blood neovascularization and lymphangiogenesis in the cornea are VEGF-A and VEGF-C, respectively. NEI investigators have found that, among the many inhibitors of neovascularization that reside in the cornea, soluble VEGFR-1 acts as a trap for VEGF-A to promote corneal avascularity. Investigators are working to develop and evaluate anti-neovascular agents that inhibit neovascularization. In contrast, the molecular basis of the alymphatic cornea has not been resolved. Indeed, no endogenous specific inhibitor of lymphangiogenesis in any tissue has yet been reported. However, a recent study found that a variant of VEGFR-2 plays a role in inhibiting injury-induced lymphangiogenesis and reduced corneal graft rejection in rodent models. NEI investigators are currently evaluating the expression and function of this VEGFR-2 variant during development and to discover the underlying molecular mechanisms by which this receptor inhibits lymphangiogenesis. These studies will help lead to the development of novel therapeutics that can prevent neovascularization and lymphangiogenesis.

Research accomplishments in corneal transplantation include:

Older corneas have similar survival rates in corneal transplantation, making them a suitable source of donor tissue.

Tissue engineers have developed improved methods of manipulating collagen to produce a clear, transparent corneal membrane.

Investigators have had success in increasing the proliferative ability of human corneal endothelial cells. Successful completion of this work could increase available supply of donor corneal tissue.

The underlying immune mechanisms that promote graft rejection in corneal transplants have become better understood.

Improved imaging technologies are enabling investigators to better quantify the pathological features that promote neovascularization of the cornea. This work will help identify high-risk patients who might be candidates for anti-neovascular therapies.

NEI investigators have identified the underlying molecular mechanisms that control neovascularization and lymphangiogenesis in the cornea. This work will enable the development of therapies that inhibit the pathology that leads to graft rejection.

We welcome your questions and comments. Please send general questions and comments to the NEI Office of Science Communications, Public Liaison, and Education. Technical questions about this website can be addressed to the NEI Website Manager.